Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System

NICHOLAS BRANDON works at AstraZeneca within the Neuroscience Innovative Medicines Group. He has spent his career in drug discovery with a strong interest in developing phosphodiesterase inhibitors for neuropsychiatric disorders and understanding the basic mechanisms of phosphodiesterase function. ANTHONY WEST is an Associate Professor in the Department of Neuroscience at Rosalind Franklin University. He has studied PDE function in the basal ganglia for over fifteen years, focusing on neurochemical and electrophysiological changes induced by PDE inhibitors in the healthy brain and in animal models of Parkinson’s disease and Huntington’s disease.

PREFACE vii

CONTRIBUTORS ix

1 PHOSPHODIESTERASES AND CYCLIC NUCLEOTIDE SIGNALING IN THE CNS 1
Marco Conti and Wito Richter

2 PUTTING TOGETHER THE PIECES OF PHOSPHODIESTERASE DISTRIBUTION PATTERNS IN THE BRAIN: A JIGSAW PUZZLE OF CYCLIC NUCLEOTIDE REGULATION 47
Michy P. Kelly

3 COMPARTMENTALIZATION AND REGULATION OF CYCLIC NUCLEOTIDE SIGNALING IN THE CNS 59
Manuela Zaccolo and Alessandra Stangherlin

4 PHARMACOLOGICAL MANIPULATION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE SIGNALING FOR THE TREATMENT OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS IN THE BRAIN 77
Frank S. Menniti, Niels Plath, Niels Svenstrup, and Christopher J. Schmidt

5 RECENT RESULTS IN PHOSPHODIESTERASE INHIBITOR DEVELOPMENT AND CNS APPLICATIONS 115
David P. Rotella

6 CRYSTAL STRUCTURES OF PHOSPHODIESTERASES AND IMPLICATION ON DISCOVERY OF INHIBITORS 145
Hengming Ke, Huanchen Wang, Mengchun Ye, and Yingchun Huang

7 INHIBITION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASES TO REGULATE MEMORY 171
Han-Ting Zhang, Ying Xu, and James O’Donnell

8 EMERGING ROLE FOR PDE4 IN NEUROPSYCHIATRIC DISORDERS: TRANSLATING ADVANCES FROM GENETIC STUDIES INTO RELEVANT THERAPEUTIC STRATEGIES 211
Sandra P. Zoubovsky, Nicholas J. Brandon, and Akira Sawa

9 BEYOND ERECTILE DYSFUNCTION: UNDERSTANDING PDE5 ACTIVITY IN THE CENTRAL NERVOUS SYSTEM 223
Eva P.P. Bollen, Kris Rutten, Olga A.H. Reneerkens, Harry M.W. Steinbusch, and Jos Prickaerts

10 MOLECULAR AND CELLULAR UNDERSTANDING OF PDE10A: A DUAL-SUBSTRATE PHOSPHODIESTERASE WITH THERAPEUTIC POTENTIAL TO MODULATE BASAL GANGLIA FUNCTION 247
Erik I. Charych and Nicholas J. Brandon

11 ROLE OF CYCLIC NUCLEOTIDE SIGNALING AND PHOSPHODIESTERASE ACTIVATION IN THE
MODULATION OF ELECTROPHYSIOLOGICAL ACTIVITY OF CENTRAL NEURONS 269
Sarah Threlfell and Anthony R. West

12 THE ROLE OF PHOSPHODIESTERASES IN DOPAMINE SYSTEMS GOVERNING MOTIVATED BEHAVIOR 303
Gretchen L. Snyder, Joseph P. Hendrick, and Akinori Nishi

13 INHIBITION OF PHOSPHODIESTERASES AS A STRATEGY FOR TREATMENT OF SPINAL CORD INJURY 353
Elena Nikulina and Marie T. Filbin

INDEX 375